Studies over the past 15 years suggest that the prevailing rate of epilepsy in the United States is between 5 and 20 per 1000, and recent estimates drawn from population surveys indicate that the higher rates are closer to the true prevalence. This means that 1 to 4 million Americans suffer from some form of epilepsy. For certain types of seizures there are no specific drugs available; for seizures that are controlled with currently available therapy, a new drug may allow a reduction in the toxic side effects. Despite these facts, between 1960 and 1974, no new anticonvulsant drug was marketed in the United States (with the exception of diazepam, which was marketed primarily as a minor tranquilizer) (Vida, J. A. "Anticonvulsants," Academic Press, New York, 1977). However, since the approval of carbamazepine in 1974 and clonazepam in 1975, and sodium dipropylacetate, eterobarb, mexiletine and others in 1977-1978, there has been a resurgence of interest in the development of better anticonvulsant drugs for the management of epilepsy. Also responsible for this renewed interest is the establishment of the Anticonvulsant Screening Project of the Antiepileptic Drug Development (ADD) Program of NINCDS (National Institute of Neurological and Communicative Disorders and Stroke) of NIH, in January, 1975.
In recent years hundreds of different heterocyclic compounds have been synthesized and screened for anticonvulsant activity. These include mostly five and six membered ring systems containing up to three or four heteroatoms and seven membered ring systems related to the diazepines. Among the nitrogen containing heterocycles, a considerable amount of work has been done in the areas of five membered rings bearing one or two nitrogen atoms.
Five membered rings with 3 or 4 nitrogen atoms that have been investigated, include mostly, 1,2,4-triazoles and some tetrazoles. Very little has been done on 1,2,3-triazoles (Popp, F. D., In "Anticonvulsants," J. A. Vida, Ed. Academic Press, New York, 1977). The literature indicates that to date there are no references to any published work relating to studies on the anticonvulsant activity of triazolines.
The 1,2,3-triazolines are a novel group of anticonvulsant compounds because their heterocyclic ring system is different from that of conventional anticonvulsant drugs. The presently marketed antiepileptic drugs, for the major part, have a dicarboximide function and/or a disubstituted quaternary carbon group (barbiturates, hydantoins, succinimides, oxazolidinediones) or closely related structure (primidone). On the other hand, the dicarboximide function, which contributes to the inherent hypnotic and sedative activity of the barbiturates and related compounds, is absent in the triazolines.
Triazolines including .DELTA..sup.2 -1,2,3-triazolines, are known to some extent in the prior art, through applicant's own publications of work in this area. None of the triazolines, however, has been suggested heretofore for use as anticonvulsants.
As indicated, the present applicant has published a number of papers involving her work on triazolines. The following publications discuss primarily the use of triazolines as intermediates in providing a route for the synthesis of certain anilinopyridazines and pyrazoles, (Kadaba, P. K., and Triplett, J. "Heterocycles, An International Journal for Reviews and Communications in Heterocyclic Chemistry," Vol. 9, No. 3, 1978, pp. 243-246) and triazoles (Kadaba, P. K. "Synthesis, International Journal of Methods in Synthetic Organic Chemistry," No. 9: Stepember, 1978, pp. 694-695.)
The following publications describe the results of screening or evaluation of triazolines for pesticide and herbicide properties. (Kadaba, P. K., "Pestic. Sci.," 1974, 5, pp. 255-258. ) (Kadaba, P. K., "Journal of Pharmaceutical Sciences," Vol. 59, No. 8, 1970, pp. 1190-91. )
The following publications primarily describe procedures for the production of triazolines through cycloaddition of diazomethane to Schiff bases and solvent effects on this reaction as well as steric effects. (Kadaba, P. K., and Edwards, J. "Journal of Organic Chemistry, 26, 1961, pp. 2331-2335. ) (Kadaba, P. K., "Tetrahedron, Vol. 22, 1966, pp. 2453-2460. ) (Kadaba, P. K., and Fannin, N., "Journal of Heterocyclic Chemistry," 4, 1967, pp. 301-304. ) (Kadaba, P. K., "Journal of Heterocyclic Chemistry, 6, 1969, pp. 587-589. ) (Kadaba, P. K. "Tetrahedron, Vol. 25, 1969, pp. 3053-3066. ) (Kadaba, P. K., "Synthesis, International Journal of Methods in Synthetic Organic Chemistry, No. 2: February, 1973, pp. 71-84. ) (Kadaba, P. K., "Journal of Heterocyclic Chemistry, 12, 1975, pp. 143-146. ) (Kadaba, P. K., "Journal of Heterocyclic Chemistry, 13, 1976, pp. 1153-54. )
In none of these publications, however, is there any disclosure of use of any of the 1,2,3 triazoline compounds as anticonvulsants.